Bioerodible Composites for Endoprostheses

ABSTRACT

A bioerodible endoprosthesis includes a composite including a matrix comprising a bioerodible magnesium alloy and a plurality of ceramic nanoparticles within the matrix. The bioerodible magnesium alloy has a microstructure including equiaxed Mg-rich solid solution-phase grains having an average grain diameter of less than or equal to 5 microns. The microstructure can be produced by one or more equal-channel high-strain processes.

TECHNICAL FIELD

This disclosure relates to bioerodible composites used in endoprosthesesand methods of producing those composites.

BACKGROUND

Endoprostheses can be used to replace a missing biological structure,support a damaged biological structure, and/or enhance an existingbiological structure. Frequently, only a temporary presence of theendoprosthesis in the body is necessary to fulfill the medical purpose.Surgical intervention to remove endoprostheses, however, can causecomplications and may not even be possible. One approach for avoiding apermanent presence of all or part of an endoprosthesis is to form all orpart of the endoprosthesis out of bioerodible material. The term“bioerodible” as used herein is understood as the sum of microbialprocedures or processes solely caused by the presence of endoprosthesiswithin a body, which results in a gradual erosion of the structureformed of the bioerodible material.

At a specific time, the endoprosthesis, or at least the part of theendoprosthesis that includes the bioerodible material, loses itsmechanical integrity. The erosion products are mainly absorbed by thebody, although small residues can remain under certain conditions. Avariety of different bioerodible polymers (both natural and synthetic)and bioerodible metals (particularly magnesium and iron) have beendeveloped and are under consideration as candidate materials forparticular types of endoprostheses. Many of these bioerodible materials,however, have significant drawbacks. These drawbacks include the erosionproducts, both in type and in rate of release, as well as the mechanicalproperties of the material.

SUMMARY

A bioerodible endoprosthesis provided herein includes a compositeincluding a matrix comprising a bioerodible magnesium alloy and ceramicnanoparticles dispersed within the matrix. The bioerodible magnesiumalloy can have a microstructure defined by equiaxed Mg-rich solidsolution-phase grains (i.e., alpha-phase grains) having an average graindiameter of less than or equal to 5 microns. In some cases, the ceramicnanoparticles can be located in grain boundaries between the equiaxedMg-rich solid solution-phase grains. In some cases, the ceramicnanoparticles can have an average longest dimension of 500 nanometers orless. Bioerodible magnesium alloys having the microstructures providedherein can have improved mechanical properties suitable forendoprostheses, such as stents.

A method of processing a bioerodible magnesium alloy for endoprosthesesprovided herein can include the steps of dispersing ceramicnanoparticles within a molten magnesium alloy, cooling the magnesiumalloy and ceramic nanoparticle mixture to form an ingot or billet, andperforming at least one high-strain process on the ingot or billet toform the composite microstructure provided herein. In some cases, theprocessing can include holding the ingot or billet at a temperatureabove the solvus temperature (e.g., between 400° C. and 450° C.) for atleast 2 hours to homogenize the ingot or billet prior to performing theat least one high-strain process. The at least one high-strain processcan be an equal-channel high-strain process and can be conducted at atemperature of less than the solvus temperature (e.g., a temperaturebelow 400° C.). In some cases, multiple equal-channel high-strainprocesses are conducted using subsequently lower temperatures. Anysuitable bioerodible magnesium alloy formulation capable of havingmagnesium-rich solid solution grains can be used in the bioerodibleendoprostheses provided herein. In some cases, the bioerodible magnesiumalloy can include aluminum, zinc, calcium, manganese, tin, neodymium,yttrium, cerium, lanthanum, gadolinium, or a combination thereof. Forexample, the bioerodible magnesium alloy can include greater than 85weight percent magnesium, between 3 and 9 weight percent aluminum,between 0.1 and 3.0 weight percent zinc, less than or equal to 0.3weight percent manganese, and between 0.6 and 1.5 weight percentneodymium.

Ceramic nanoparticles included in the endoprostheses and methodsprovided herein can include any suitable ceramic material. In somecases, the ceramic nanoparticles can be insoluble in the bioerodiblemagnesium alloy. In some cases, ceramic nanoparticles can include one ormore of the following ceramic materials: TiC, TiO₂ Si₃N₄, AlN, Al₂O₃,CeO₂, Boron Nitride, B₄C, and Y₂O₃.

Endorprostheses provided herein can have any suitable structure. In somecases, an endoprostheis provided herein is a stent. For example, a stentprovided herein can include plurality of struts arranged to form agenerally tubular structure that can be expanded or retracted between aplurality of different diameters. In some cases, an endoprosthesisprovided herein can consist of a composite material provided herein. Insome cases, an endorposthesis provided herein can include one or moreadditional materials. For example, in some cases an endoprosthesisprovided herein can include a coating. In some cases, a coating providedon an endoprosthesis provided herein has a thickness of between 5 nm and20 nm. In some cases, a coating provided on an endoprosthesis providedherein includes titanium oxide, aluminum oxide, or a combinationthereof. In some cases, a coating provided on an endoprosthesis providedherein includes a therapeutic agent.

One advantage of an endoprosthesis including a composite provided hereinis that the resulting endoprosthesis' mechanical properties anddegradation rate can be tailored to maintain desired mechanicalproperties over a desired period of time and an optimal bioerosion rate.A bioerodible magnesium alloy having a microstructure provided hereincan have improved ductility as compared to similar alloys havingdifferent microstructures. In some cases, ceramic nanoparticles providedin the composite provided herein can simplify a grain refinementprocedure by pinching grain boundaries and inhibiting grain growthduring one or more high-strain processes.

The details of one or more embodiments are set forth in the accompanyingdrawings and the description below. Other features, objects, andadvantages will be apparent from the description and drawings, and fromthe claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a perspective view of a representative stent.

FIG. 2 depicts an exemplary arrangement for fabricating amagnesium-alloy ceramic-nanoparticle composite.

FIG. 3 depicts an exemplary Equal-Channel Angular Extrusion die.

DETAILED DESCRIPTION

A stent 20, shown in FIG. 1, is an example of an endoprosthesis. Stent20 includes a pattern of interconnected struts forming a structure thatcontacts a body lumen wall to maintain the patency of the body lumen.For example, stent 20 can have the form of a tubular member defined by aplurality of bands 22 and a plurality of connectors 24 that extendbetween and connect adjacent bands. During use, bands 22 can be expandedfrom an initial, small diameter to a larger diameter to contact stent 20against a wall of a vessel, thereby maintaining the patency of thevessel. Connectors 24 can provide stent 20 with flexibility andconformability that allow the stent to adapt to the contours of thevessel. Other examples of endoprostheses include covered stents andstent-grafts.

At least one strut of stent 20 can be adapted to erode underphysiological conditions. In some cases, stent 20 is fully bioerodible.Stent 20 can include a composite of a matrix including a bioerodiblemagnesium alloy and ceramic nanoparticles within the matrix. Abioerodible magnesium alloy used in a composite provided herein caninclude additional elements, such as aluminum, zinc, and neodymium. Abioerodible magnesium alloy used in a composite provided herein can havea microstructure defined by relatively equiaxed magnesium-rich solidsolution-phase grains having an average grain diameter of less than orequal to 5 microns (longest dimension in a metallography cross-sectionplane).

Ceramic nanoparticles used in a composite provided herein can have anaverage diameter of less than 500 nanometers. In some cases, ceramicnanoparticles used in a composite provided herein can have an averagediameter of between 0.5 nanometers and 500 nanometers, between 1nanometer and 200 nanometers, between 5 nanometers and 100 nanometers,or between 10 nanometers and 75 nanometers. In some cases, the ceramicnanoparticles in a composite provided herein can be predominantlylocated in grain boundaries rather than within grains (e.g., >50% of thecombined area of ceramic nanoparticles are on grain boundaries in agiven prepared metallography cross-section plane examined at 100-300×magnification). Composites having the microstructures provided hereincan have improved mechanical properties suitable for endoprostheses,such as stents.

Although magnesium and magnesium alloys have been explored as candidatematerials for bioerodible endoprostheses in the past, the mechanicalproperties of magnesium and magnesium alloys have presented certaindifficulties that make the use of a bioerodible magnesium metal or alloyin certain endoprostheses, such as stents, impractical. In particular,magnesium alloys can have a limited ductility due to a lack of availableslip planes in the Hexagonal Close Packed (HCP) crystal lattice. Slipplanes can accommodate plastic deformation. Limited ductility cancomplicate certain uses that rely upon plastic deformation. For example,limited ductility can make stent crimping and stent expansion morecomplex due to an increased probability of stent fractures during theseplastic deformations. Moreover, magnesium alloys typically have a lowertensile strength than iron alloys (such as stainless steel alloys).Composites provided herein, however, can have improved ductility andtensile strength.

Certain magnesium alloys were tested in order to identify magnesiumalloys having suitable bioerosion rates and ductility. For example, L1cand WE43 (described in Table I below) were prototyped and tested asstents, but found to have a bioerosion rate that was too fast whensubjected to in-vivo and in-vitro testing. It is possible, however, thata L1c and/or WE43 alloy having a microstructure provided herein wouldhave a suitable bioerodison rate for an endoprosthesis.

TABLE I Alloy Other Ex. Zn Zr Mn Y Ca Ag Fe Elements Mg L1c 2.87 ≦0.020.15 — 0.22 0.10 0.0036 — Balance WE43 0.20 0.36 0.13 4.16 — — — 3.8091.35

Certain modifications of the AZ80 alloy (see Table II below) have alsobeen developed in an attempt to find a magnesium alloy having superiorcorrosion resistance to that of L1c, but also having sufficientductility. Although initial mechanical testing of these AZ80 modifiedalloys showed an improvement in the mechanical and corrosion propertiesas compared to L1c, AZ80 modified alloy stents cracked and fractured ata nominal expanded diameter.

TABLE II Alloy Example Al Zn Mn Y Nd La Mg AZ80 7.5 0.5 0.2 — — —Balance AZNd 7.3 0.6 0.1 — 0.7 — Balance AZY 7.4 0.6 0.1 0.5 — — BalanceAZNdY 7.0 0.6 0.2 0.5 0.6 — Balance AZM 7.3 0.6 0.4 — — — Balance AZL7.0 0.5 0.2 — — 1.2 Balance AE82 8.0 0.5 0.2 0.5 1.0 — Balance

An analysis of the stents identified the presence of large extrinsicintermetallic particles, e.g., oxide inclusions and coarse Mg solidsolution grain sizes, which are deleterious to ductility. Low materialductility can result in stent cracking, especially in balloon-expandablestents that are crimped onto a balloon catheter, guided through a longtortuous path, and expanded to fill the diameter of the artery.

Composite microstructures and processes provided herein can eliminatethis root cause of low material ductility and stent cracking by havinglower extrinsic inclusion content (or at least much smaller inclusions)and stent material with refined Mg solid solution grain size torandomize grain texture, produce additional slip systems through grainsize refinement, and raise the activation energy needed to initiate acrack due to the presence of a tortuous grain boundary network.Composite microstructures and processes provided herein can be tailoredto manifest sufficient ductility in a balloon-expandable stent designsuch that the Mg alloy stent would allow the stent to be crimped onto aballoon catheter, wiggled through a long tortuous path, and expanded tofill the diameter of the artery without fracturing.

The microstructure of material can be at least partially dependent onthe processing techniques and parameters. The grains (i.e., crystals) ofa magnesium alloy can align themselves with their basal planes parallelto the direction of the processing material flow, which can result indifferent mechanical properties in the direction of flow as compared tothe a direction perpendicular to the direction of flow. In the case ofextruding stent tubing including the alloys of Table II, the resultingtube may have a strong preferred crystal orientation, aligning the basalplanes in the extrusion direction, which produces increased ductility inthe extrusion direction of the tubing, but less ductility in a directionperpendicular to the extrusion direction. The expansion of a stent,however, relies upon the material having suitable ductility in alldirections. A strong grain texture with an unfavorable loading along thec-crystal axis components of the grains causes twinning and voidnucleation under lower strains. The twinning with void nucleation can bethe initiation of an eventual material failure. Stent tube extrusion mayalso produce a randomized crystal structure with no preferredorientation, which produces more isotropic mechanical properties, butstill suffers from the ductility issues discussed above.

Composites provided herein can provide superior ductility and othermechanical properties in multiple directions. Ceramic nanoparticles canbe dispersed within a matrix of a bioerodible magnesium alloy. Ceramicnanoparticles can pinch grain boundaries and/or impede grain growthduring processing of the material, which can result in a fine grainmicrostructure of the magnesium alloy. The fine grain microstructure ofthe magnesium alloy can increase strength and ductility of thecomposite. In some cases, the grain boundaries can be decorated withceramic nanoparticles. In some cases, the magnesium alloy can furtherinclude beta-phase precipitates, which can also decorate grainboundaries. The microstructures provided herein can be characterized ina number of ways. In some cases, the microstructures provided herein,when viewed at a 500× using x-ray diffraction, have no more than 5% byarea filled with ceramic particles. In some case, the microstructuresprovided herein have no more than 3% by area filled with ceramicparticles. In some case, the microstructures provided herein have nomore than 2% by area filled with ceramic particles. In some case, themicrostructures provided herein have at least 0.5% by area filled withceramic particles. In some case, the microstructures provided hereinhave at least 1.0% by area filled with ceramic particles. In some case,the microstructures provided herein have between 0.5% and 5% by areafilled with ceramic particles. In some case, the microstructuresprovided herein have between 1.0% and 3% by area filled with ceramicparticles. In some case, the microstructures provided herein have about1.5% by area filled with ceramic particles.

Ceramic nanoparticles provided in a composite provided herein can haveany appropriate dimensions. In some cases, ceramic nanoparticles used ina composite provided herein have an average largest diameter of between0.5 nanometers and 500 nanometers, between 1.0 nanometer and 200nanometers, between 5 nanometers and 100 nanometers, between 10nanometers and 100 nanometers, between 25 nanometers and 75 nanometers,or between 40 nanometers and 60 nanometers. In some cases, a maximumceramic nanoparticle dimension will be 5 micron or less. In some cases,a maximum ceramic nanoparticle dimension will be 1 micron or less, 500nanometers or less, 5 microns or less, or 200 nanometers or less.

Ceramic nanoparticles provided in a composite provided herein caninclude any suitable ceramic material. In some cases ceramicnanoparticles provided herein are insoluble in a magnesium alloy used ina composite provided herein. In some cases, ceramic nanoparticles caninclude one or more of the following ceramic materials: TiC, TiO₂ Si₃N₄,AlN, Al₂O₃, CeO₂, Boron Nitride, B₄C, and Y₂O₃. In some cases, ceramicnanoparticles used in a composite provided herein include a radiopaqueceramic material. In some cases, ceramic nanoparticles used in acomposite provided herein can have an electro-motive force within 50% ofthe electro-motive force of magnesium. In some cases, ceramicnanoparticles used in a composite provided herein can have anelectro-motive force within 25% of the electro-motive force ofmagnesium. In some cases, ceramic nanoparticles used in a compositeprovided herein can have an electro-motive force within 10% of theelectro-motive force of magnesium. In some cases, ceramic nanoparticlesused in a composite provided herein can have an electro-motive forcewithin 5% of the electro-motive force of magnesium. Suitable ceramicnanoparticles are available from SkySpring Nanomaterials, Houston Tex.

The microstructures provided herein can include equiaxed Mg-rich solidsolution-phase grains with ceramic nanoparticles located within smoothand equiaxed alpha-phase-grain boundaries. In some cases, the equiaxedequiaxed Mg-rich solid solution-phase grains have an average grain sizeof 20 microns or less, 15 microns or less, 10 microns or less, 7.5microns or less, 5 microns or less, 4 microns or less, 3 microns orless, 2 microns or less, or 1 microns or less. In some cases, theequiaxed Mg-rich solid solution-phase grains have an average grain sizeof between 0.1 microns and 10 microns, of between 0.5 microns and 5microns, or between 1 micron and 4 microns. In some cases, at least 90%by volume of the ceramic nanoparticles can be found along alpha phasegrain boundaries. In some cases, the average ceramic nanoparticlediameter or longest dimension is 1 microns or less, 500 nanometers orless, 300 nanometers or less, 200 nanometers or less, 100 nanometers orless, 75 nanometers or less, 50 nanometers or less, or 25 nanometers orless. In some cases, the average ceramic nanoparticle diameter orlongest dimension is between 0.1 nanometers and 1 micron, between 0.5nanometer and 500 nanometers, between 5 nanometers and 300 nanometers,between 10 nanometers and 200 nanometers, between 20 nanometers and 100nanometers, between 25 nanometers and 75 nanometers, or between 40nanometers and 60 nanometers. The microstructure provided herein canhave a reduced number of twin bands. In some cases, less than 15% of thealpha grains will have twin bands. In some cases, the number of alphagrains having twin bands can be less than 10%, less than 5%, or lessthan 1% when the stent is cut and crimped.

Composites having microstructures provided herein can have enhancedductility. The microstructures provided herein can overcome the basalplane alignment by randomizing grain orientations and result inisotropic mechanical properties. Finer grains also yield increased grainboundary areas, which can provide more grain boundary slip. Refinementof precipitate diameter may also allow additional grain boundary slip.Moreover, a homogenous dispersion of ceramic nanoparticles along thegrain boundaries can improve strength and corrosion resistance. In somecases, the ceramic nanoparticles can be substantially centered on thegrain boundary but be larger than the width of the grain boundary.

For example, a tubular body (e.g., stent tubing material) made from acomposite of an AZNd alloy and 1.5 percent by volume of ceramicnanoparticles (e.g., SiC nanoparticles) can be made by a process asdescribed below. The AZNd alloy can include between 3 weight percent and9 weight percent aluminum, between 0.1 weight percent and 1.0 weightpercent zinc, and between 0.1 weight percent and 1.5 weight percentneodymium. The composite can have an elastic modulus of between 39 and200 GPa, a 0.2% Offset Yield Strength of between 150 and 600 MPa, anultimate tensile strength of between 225 and 600 MPa, a tensilereduction in area (RIA) of between 30% and 80%. In some cases, stenttubing material provided herein can have a tensile RIA of between 45%and 80%. In some cases, stent tubing material provided herein canmaintain its initial elastic modulus, Yield Strength, ultimate tensilestrength, and a tensile RIA within +/−10% after storage of the tubingfor 180 days at a temperature of between 20° C. and 25° C. and arelative humidity of less than 30%.

Composites having a microstructure provided herein can be polished tohave a smooth surface finish. In some cases, an endoprosthesis providedherein can have a surface including a bioerodible magnesium alloy havinga surface roughness R_(a) of less than 0.5 microns, less than 0.4microns, less than 0.3 microns, less than 0.2 microns, less than 0.1microns, or less than 0.05 microns. Composites provided herein can haveimproved corrosion resistance, which can provide a slower bioerosionrate. A stent body including a composite material provided herein canhave an in-vitro corrosion penetration rate of less than 200 μm/yearafter a period of 28 days of continuous immersion in non-flowing,agitated Simulated Body Fluid (agitated at 60 rpm) at 37° C. where theSimulated Body Fluid (“SBF”) is present in an amount of at least 10times the initial volume of the stent material. The ingredients of SBF,which are added to water, are shown in Table 3.

TABLE 3 SBF Ingredients Chemical Mass/Volume NaCl 5.403 g NaHCO₃ 0.504 gNa₂CO₃ 0.426 g KCl 0.225 g K₂HPO₄•3H₂O 0.230 g MgCl₂•6H₂O 0.311 g 0.2MNaOH 100 mL HEPES 17.892 g CaCl₂ 0.293 g Na₂SO₄ 0.072 g

In some cases, the magnesium alloy includes aluminum. Aluminum can formnative oxide layers along grain boundaries, which can act as aprotective layer for the grains and delay the onset of intergranularcorrosion. Smaller grain sizes can also reduce the corrosion ratebecause corrosion must re-initiate past the protective oxide layer foreach grain corroded.

Composites provided herein can be formed by using the following processsteps: (a) disperse ceramic nanoparticles in a molten magnesium alloy;(b) cooling the molten magnesium alloy to form a ingot or billet; (c)solution treating a billet to solutionize any intermetallic precipitatesformed during solidification of the alloy; (d) controlled cooling aftersolutionizing to form a distribution of precipitates (if any) alonggrain boundaries; and (e) thermomechanical deformation of the compositeafter or during cooling to refine the Mg-rich solid solution grain sizeand produce a substantially equiaxed grain morphology.

Ceramic nanoparticles can be dispersed within a molten magnesium alloyusing any suitable method. FIG. 2 depicts an exemplary arrangement 200for introducing ceramic nanoparticles 210 into a molten magnesium alloy220. Magnesium metal and one or more alloying constituents (e.g.,aluminum) can be introduced to a steel crucible 202 within a resistancefurnace 204. In some case, magnesium is alloyed with alloying elementsprior to introduction to steel crucible 202 or resistance furnace 204.In some cases, magnesium is alloyed with alloying elements in steelcrucible 202 before, after, or concurrently with an addition of ceramicnanoparticles. A protection gas 206 can be used to prevent unwantedreactions or exposure to oxygen. In some cases, energy can be used toprevent ceramic nanoparticles from agglomerating during the mixingprocess. For example, an ultrasonic probe 230 can be placed within steelcrucible 202 to impart ultrasonic energy to the mixture. The mixture canthen be cooled to form a billet or ingot. For example, an ingot orbillet can be formed or machined into a solid or hollow rod,homogenized, subjected to a high-strain process to refine themicrostructure, and then shaped or machined into stent tubing from whichthe stent is manufactured into final dimensions (e.g., the dimensions ofa stent body). In some cases, a billet or ingot provided herein can beformed into an endoprosthesis that does not normally undergo expansion,for example vascular closing plugs or embolical material (e.g.,microbeads used to close off unwanted vascular structures or canceroustissue).

Billets can be made using any suitable process. A billet can have adiameter of between 2 centimeters and 1 meter. In some cases, an ingotof a desired bioerodible magnesium alloy can be made by conventionalmelting and solidification in a mold (liquid casting), thixomolding(semi-solid processing) or powder metallurgy (solid-processing). Theingot can then be machined to the desired dimensions of the billet whichwill serve as the feedstock for subsequent processing and shaping. Insome cases, a billet can be formed without additional machining process.To form an endoprosthesis (e.g., a stent body) including a compositeprovided herein out of a billet, the billet can be converted into a rodor hollow tube having a smaller diameter. In some cases, the ingot orbillet is converted into a rod or hollow tube after the ingot or billetis homogenized. In some cases, the rod or hollow tube can have an outerdiameter of between 1 centimeter and 6 centimeters. In the case of astent, a hollow tube of a composite provided herein can then be furtherreduced in diameter and cut to form individual stent bodies, includingfenestrations between stent struts. In some cases, the stent struts canhave a width to thickness ratio of less than 1.2. In some cases, thethickness of the hollow tube and the stent struts can be between 80microns and 160 microns.

An ingot or billet, in some cases, can be made by thixomolding theelements of the bioerodible magnesium alloy and ceramic nanoparticles.Thixomolding involves mixing solid constituents into a portion of thecomposition that is in a liquid phase and then cooling the mixture toreach a fully solid state. Thixomolding can reduce the number and sizeof brittle inter-metallic (IM) particles in the alloy. For example,thixomolding can use a machine similar to an injection mold. Roomtemperature magnesium alloy chips, chips of the other alloyconstituents, and ceramic nanoparticles can be fed into a heated barrelthrough a volumetric feeder. The heated barrel can be filled with aninert gas (e.g., argon) to prevent oxidation of the magnesium chips. Ascrew feeder located inside the barrel can feed the magnesium chips andother alloy constituents forward as they are heated into a semi-solidtemperature range. For example, the mixture can be heated to atemperature of about 442° C. The screw rotation can provide a shearingforce that can further reduce the size of IM particles. Once enoughslurry has accumulated, the screw can move forward to inject the slurryinto a steel die having the shape of an ingot or billet.

An ingot or billet, in some cases, can be made by combining the elementsof the bioerodible magnesium alloy using powder metallurgy. Powdermetallurgy involves the solid-state sintering of elemental orpre-alloyed powder particles and ceramic nanoparticles. Using finepowders in a sintering process can avoid the formation of coarse IMparticles. For example, fine powders of magnesium, other alloyingconstituents, and ceramic nanoparticles can be blended into a homogenousmixture, pressed into a desired shape (e.g., the shape of the ingot orbillet), and heated while compressed to bond the powders together.Sintering can be conducted in an inert atmosphere (e.g., argon) to avoidoxidation of the magnesium.

An ingot or billet including all of the desired elements of abioerodible magnesium alloy and the ceramic nanoparticles can behomogenized to reduce elemental concentration gradients. The ingot orbillet can be homogenized by heating the ingot or billet to an elevatedtemperature below the liquidus temperature of the bioerodible magnesiumalloy and holding the ingot or billet at that temperature for period oftime sufficient to allow elemental diffusion within the ingot or billetto reduce elemental concentration gradients within the ingot or billet.

Homogenizing the ingot or billet can solutionize intermetallic (IM)second-phase precipitate particles, because the homogenizationtemperature is in excess of the phase boundary (solvus temperature)between the high-temperature single, solid phase (alpha) and two-phasefield boundary on the Mg—Al phase diagram. A follow-on solutioningtreatment at the same or similar position within the phase diagram canbe used in some cases to refine the precipitate structure. For example,a follow-on solutioning treatment can be used if the homogenizationtreatment cooling was not controlled sufficiently to tailor thesecond-phase precipitate size and location. In some cases, the ingot orbillet is cooled rapidly after holding the ingot or billet at theelevated temperature in order to form relatively fine IM ceramicnanoparticles. For example, the ingot or billet can be cooled from theelevated hold temperature via force gas cooling or liquid quenching. Theingot or billet can be homogenized in an inert atmosphere (e.g., in anargon atmosphere) or open atmosphere so long as surface oxides areremoved. In some cases, the ingot or billet provided herein can behomogenized at a temperature of between 400° C. and 450° C. In somecases, the ingot or billet is held at a temperature of between 400° C.and 450° C. for at least 2 hours, at least 3 hours, or at least 4 hours.In some cases, the hold time at an elevated temperature is between 4hours and 24 hours. For example, a bioerodible magnesium alloy ingothaving a diameter of about 15 centimeters can be heated to a temperatureof 440° C. for 6 hours to homogenize the ingot, followed by quenchingthe ingot in a cooled argon gas stream.

An ingot or billet can be subjected to one or more high-strain processesto refine the microstructure into a microstructure provided herein. Insome cases, the high-strain process(es) can include one or moreequal-channel high-strain processes. Equal-channel high-strain processesinclude Equal-Channel Angular Extrusion (“ECAE”) and Equal-ChannelAngular Pressing (“ECAP”). ECAE is an extrusion process that producessignificant deformation strain without reducing the cross sectional areaof the piece. ECAE can be accomplished by extruding a compositeincluding a magnesium alloy and ceramic nanoparticles (e.g., a billet ofthe material) around a corner. For example, a billet can be forcedthrough a channel having a 90 degree angle. The cross section of thechannel can be equal on entry and exit. The complex deformation of thecomposite as it flows around the corner can produce very high strains inthe bioerodible magnesium alloy. In some cases, an ingot can be machinedinto a billet having the exact dimensions of the channel of an ECAE dieprior to an ECAE process. Because the cross section can remain the same,the billet can be extruded multiple times with each pass introducingadditional strain. With each ECAE process, the orientation of the billetcan be changed to introduce strain along different planes. In somecases, an ECAE die can include multiple bends. For example, FIG. 3depict an example of an ECAE die.

The ingot or billet provided herein can be extruded through one or moreECEA dies (e.g., as depicted in FIG. 3) at temperatures lower than ahomogenization temperature. Multiple equal-channel high-strainextrusions can be performed at subsequently lower temperatures. Theequal-channel high-strain processes can yield a fine grain size. Ceramicnanoparticles in the composite can become primarily located along thegrain boundaries. In some cases, the dynamic recrystallization of thegrain refinement caused by successive equal-channel high-strainextrusions at declining temperatures can introduce more strain into thematerial and result in finer grain sizes as compared to cold working andannealing steps. In some cases, an ingot or billet is subjected to atleast two ECAE processes at two different sequentially-lowertemperatures. In some cases, an ingot or billet is subjected to at leastthree ECAE processes at different sequentially-lower temperatures.

For example, a billet including a magnesium-aluminum alloy can beprocessed through two ECAE processes, with the first ECAE processoccurring at a higher temperature than the second ECAE process. Eachprocess can occur through a simple ECAE die have a single 90° corner,such as that depicted in FIG. 3. The first ECAE process can be conductedat a temperature of between 250° C. and 400° C. to allow good diffusionof aluminum to the grain boundaries. The first ECAE process can resultin a microstructure having an average grain diameter of 15 microns orless. A second ECAE process can be done at a temperature of between 150°C. and 300° C. The second ECAE process can further refine the grainsizes and avoid coarsening.

In the ECAE process shown in FIG. 3, an ingot or prior-worked billet 30ais extruded through a channel 31a including two channel portions 32a,33a of substantially identical cross-sectional areas having therespective centerlines thereof disposed at an angle 35a. As shown, angle35a can be about 90°. In some cases, angle 35a can be between 45° and170°, between 50° and 160°, between 60° and 135°, between 70° and 120°,between 80° and 100°, or between 85° and 95°. Billet 30a can have anyappropriate cross section and machined to provide a snug fit into entrychannel portion 32a. In some cases, billet 30a can have a circular crosssectional shape. A ram 38a can force billet 30a through channel 31ausing an appropriate extrusion ram pressure. The strain imposed onbillet 30a is a function of angle 35 a.

Composites provided can, in some cases, be made by sintering powders ofmetal alloy and ceramic nanoparticles together. In some cases, powdermetallurgy techniques can be used to form a composite provided herein.

The billet can be formed into a rod or hollow tube having a reducedouter diameter after one or more high-strain processes. Tube or roddrawing from the billet can occur in multiple steps, with optionalintermediate and final annealing steps, to reduce the diameter. Thedrawing and annealing processes can be controlled to preserve themicrostructure formed in the one or more high-strain processes. In somecases, the material is annealed at a temperature of less than 300° C. Insome cases, the material is annealed at a temperature of between 150° C.and 300° C., between 150° C. and 250° C., or between 150° C. and 200° C.Annealing steps can be used to allow recovery with limitedrecrystallization and avoid grain growth or changes in precipitatevolume fraction and morphology Annealing steps can also maintain ahomogenous dispersion of beta-phase precipitates at the grainboundaries.

Individual stent bodies can then be cut, including cutting fenestrationsbetween stent struts, using any suitable technique. For example, thefenestrations can be cut using a laser.

Composites provided herein can include magnesium alloyed with anysuitable combination of additional elements. In some cases, abioerodible magnesium alloy provided herein can include aluminum. Insome cases, a bioerodible magnesium alloy provided herein can includezinc. In some cases, a bioerodible magnesium alloy provided herein caninclude calcium. In some cases, a bioerodible magnesium alloy providedherein can include tin. In some cases, a bioerodible magnesium alloyprovided herein can include manganese. In some cases, a bioerodiblemagnesium alloy provided herein can include neodymium. In some cases, abioerodible magnesium alloy provided herein can include at least 85weight percent magnesium, between 3 and 9 weight percent aluminum,between 0.1 and 3 weight percent zinc, and between 0.05 and 0.3 weightpercent manganese, between 0.6 and 1.5 weight percent neodymium, up to100 ppm copper, and up to 175 ppm iron. For example, a composite caninclude about 1.5 weigh percent ceramic nanoparticles and a bioerodiblemagnesium alloy including about 92-93 weight percent magnesium, between6.0 and 6.5 weight percent aluminum, between 0.4 and 0.5 weight percentzinc, between 0.6 and 0.7 weight percent neodymium, up to 100 ppmcopper, and up to 175 ppm iron. Other possible bioerodible magnesiumalloys include those listed in Tables I and II above. Examples of othersuitable bioerodible magnesium alloys can be found in U.S. PatentApplication Publication No. 2012/0059455, which is hereby incorporatedby reference in its entirety, particularly the sections describingparticular bioerodible magnesium alloys.

A bioerodible magnesium alloy used in a composite provided herein caninclude a variety of different additional elements. In some cases, thebioerodible magnesium alloy includes less than 5 weight percent, in sum,of elements other than magnesium, aluminum, zinc, and manganese. In somecases, the bioerodible magnesium alloy includes less than 2 weightpercent, in sum, of elements other than magnesium, aluminum, zinc, andmanganese. The bioerodible magnesium alloy can consist essentially ofmagnesium, aluminum, zinc, manganese, and neodymium. As used herein,“consisting essentially of” means that the alloy can also includeimpurities normally associated with the commercially available forms ofthe constituent elements in amounts corresponding to the amounts foundin the commercially available forms of the constituent elements. In somecases, the potential impurity elements of iron, copper, nickel, gold,cadmium, bismuth, sulfur, phosphorous, silicon, calcium, tin, lead andsodium are each maintained at levels of less than 1000 ppm. In stillother embodiments, the potential impurity elements of iron, copper,nickel, cobalt, gold, cadmium, bismuth, sulfur, phosphorous, silicon,calcium, tin, lead and sodium are each maintained at levels of less than200 ppm. Iron, nickel, copper, and cobalt have low solid-solubilitylimits in magnesium and can serve as active cathodic sites andaccelerate the erosion rate of magnesium within a physiologicalenvironment. In still other embodiments, each of iron, nickel, copper,and cobalt is maintained at levels of less than 50 ppm. For example,each of the first five alloys listed in Table II has no more than 35 ppmof iron.

Bioerodible magnesium alloys used in a composite provided herein canoptionally include one or more rare earth metals. In some cases, thebioerodible magnesium alloy includes between 0.1 and 1.5 weight percentof a first rare earth metal. In some cases, the first rare earth metalis yttrium, neodymium, lanthanum, or cerium. The bioerodible magnesiumalloy can also include between 0.1 and 1.5 weight percent of a secondrare earth metal. For example, a bioerodible magnesium alloy providedherein can include about 0.5 weight percent yttrium and 0.6 weightpercent neodymium. In some cases, the bioerodible magnesium alloyincludes three or more rare earth metals. In some cases, the totalamount of rare earth metals within the bioerodible magnesium alloy ismaintained at a level of less than 10.0 weight percent. In some cases,the total amount of rare earth metals within the bioerodible magnesiumalloy is maintained at a level of less than 2.5 weight percent.

A coating can be applied over a composite of an endoprosthesis providedherein. For example, a stent provided herein can include a stent bodyformed of a composite provided herein and a coating overlying thesurface of the stent body. A coating can slow or delay the initialdegradation of the composite upon placement within a physiologicalenvironment by serving as a temporary barrier between the magnesiumalloy and the environment. For example, delaying the bioerosionprocesses can allow the body passageway to heal and a stent to becomeendothelialized (surrounded by tissues cells of the lumen wall) beforethe strength of the stent is reduced to a point where the stent failsunder the loads associated with residing within a body lumen (e.g.,within a blood vessel). When an endothelialized stent fragments, thesegments of the stent can be contained by the lumen wall tissue and arethus less likely to be released into the blood stream.Endothelialization can also block the oxygen-rich turbulent flow of theblood stream from contacting the endoprosthesis, thus further reducingthe erosion rate of the endoprosthesis. In some case, a stent providedherein can include a coating that includes titanium oxide, aluminumoxide, or a combination thereof. Examples of suitable coatings can befound in U.S. Patent Application Publication No. 2012/0059455, which ishereby incorporate by reference in its entirety, particularly thesections describing coatings formed by atomic layer deposition.

In some cases, an endoprosthesis provided herein can include a sprayedlayer of magnesium fluoride nanoparticles. Magnesium fluoridesuspensions can be applied to an endoprosthesis provided herein using asuspension plasma spray (SPS) process, which can deliver nearlymonodisperse nanoparticles in a gram scale yield to provide a protectivemagnesium fluoride layer. The SPS process can use a Sulzer Metco TriplexII torch attached on an ABB industrial robot.

The stent can optionally include a therapeutic agent. In some cases, thecoating can include a therapeutic agent. In some cases, the coating caninclude a polymer (e.g., a bioerodible polymer). For example, adrug-eluting polymeric coating can be applied to the stent body providedherein. In some cases, a stent provided herein can be essentiallypolymer-free (allowing for the presence of any small amounts ofpolymeric materials that may have been introduced incidentally duringthe manufacturing process such that someone of ordinary skill in the artwould nevertheless consider the coating to be free of any polymericmaterial). The therapeutic agent may be any pharmaceutically acceptableagent (such as a drug), a biomolecule, a small molecule, or cells.Exemplary drugs include anti-proliferative agents such as paclitaxel,sirolimus (rapamycin), tacrolimus, everolimus, biolimus, andzotarolimus. Exemplary biomolecules include peptides, polypeptides andproteins; antibodies; oligonucleotides; nucleic acids such as double orsingle stranded DNA (including naked and cDNA), RNA, antisense nucleicacids such as antisense DNA and RNA, small interfering RNA (siRNA), andribozymes; genes; carbohydrates; angiogenic factors including growthfactors; cell cycle inhibitors; and anti-restenosis agents. Exemplarysmall molecules include hormones, nucleotides, amino acids, sugars,lipids, and compounds have a molecular weight of less than 100 kD.Exemplary cells include stem cells, progenitor cells, endothelial cells,adult cardiomyocytes, and smooth muscle cells.

A stent provided herein can include one or more imaging markers. Imagingmarkers can assist a physician with the placement of the stent. Imagingmarkers can be radiopaque marks to permit X-ray visualization of thestent.

Stent 20 can be configured for vascular, e.g., coronary and peripheralvasculature or non-vascular lumens. For example, it can be configuredfor use in the esophagus or the prostate. Other lumens include biliarylumens, hepatic lumens, pancreatic lumens, and urethral lumens.

Stent 20 can be of a desired shape and size (e.g., coronary stents,aortic stents, peripheral vascular stents, gastrointestinal stents,urology stents, tracheal/bronchial stents, and neurology stents).Depending on the application, the stent can have a diameter of between,e.g., about 1 mm to about 46 mm. In certain embodiments, a coronarystent can have an expanded diameter of from about 2 mm to about 6 mm. Insome cases, a peripheral stent can have an expanded diameter of fromabout 4 mm to about 24 mm. In certain embodiments, a gastrointestinaland/or urology stent can have an expanded diameter of from about 6 mm toabout 30 mm. In some cases, a neurology stent can have an expandeddiameter of from about 1 mm to about 12 mm. An abdominal aortic aneurysm(AAA) stent and a thoracic aortic aneurysm (TAA) stent can have adiameter from about 20 mm to about 46 mm. The stent can beballoon-expandable, self-expandable, or a combination of both (e.g., seeU.S. Pat. No. 6,290,721).

Non-limiting examples of additional endoprostheses that can include abioerodible magnesium alloy including a microstructure provided hereininclude stent grafts, heart valves, and artificial hearts. Suchendoprostheses are implanted or otherwise used in body structures,cavities, or lumens such as the vasculature, gastrointestinal tract,lymphatic system, abdomen, peritoneum, airways, esophagus, trachea,colon, rectum, biliary tract, urinary tract, prostate, brain, spine,lung, liver, heart, skeletal muscle, kidney, bladder, intestines,stomach, pancreas, ovary, uterus, cartilage, eye, bone, joints, and thelike. In some cases, an endoprosthesis can include a biodegradablescaffold for the lymphatic system.

All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference herein in their entirety.

Still further embodiments are within the scope of the following claims.

What is claimed is:
 1. A bioerodible endoprosthesis comprising: acomposite comprising a matrix comprising a bioerodible magnesium alloyand a plurality of ceramic nanoparticles within the matrix, thebioerodible magnesium alloy comprising magnesium and one or moreadditional alloying elements, the bioerodible magnesium alloy comprisingequiaxed Mg-rich solid solution phase grains.
 2. The endoprosthesis ofclaim 1, wherein the ceramic nanoparticles are primarily centered uponthe gran boundaries and do not extend into a Mg-rich solid solutionphase grain interior by more than 1 micron from the grain boundary whenviewed at 200-500× magnification on a metallography plane.
 3. Theendoprosthesis of claim 1, wherein the equiaxed Mg-rich solid solutionphase grains have an average grain diameter of less than or equal to 1micron and the ceramic nanoparticles have an average longest dimensionof between 0.5 nanometer and 200 nanometers.
 4. The endoprosthesis ofclaim 1, wherein less than 50% of the equiaxed Mg-rich solidsolution-phase grains have twin bands.
 5. The endoprosthesis of claim 4,wherein less than 15% of the equiaxed Mg-rich solid solution-phasegrains have twin bands.
 6. The endoprosthesis of claim 1, wherein thebioerodible magnesium alloy includes beta-phase precipitates.
 7. Theendoprosthesis of claim 1, wherein the ceramic nanoparticles areinsoluble in the bioerodible magnesium alloy.
 8. The endoprosthesis ofclaim 1, wherein the ceramic nanoparticles comprise a ceramic materialselected from the group consisting of TiC, Si₃N₄, AlN, Al₂O₃, CeO₂,Boron Nitride, B₄C, Y₂O₃, and combinations thereof.
 9. Theendoprosthesis of claim 1, wherein the alloy has an elastic modulus ofbetween 39 GPa and 200 GPa, a 0.2% offset yield strength of between 150MPa and 600 MPa, an ultimate tensile strength of between 250 MPa and 600MPa, and a tensile reduction in area of at least 30%
 10. Theendoprosthesis of claim 1, wherein the bioerodible magnesium alloycomprises aluminum.
 11. The endoprosthesis of claim 1, wherein thebioerodible magnesium alloy comprises zinc, calcium, manganese,neodymium, tin, yttrium, cerium, lanthanum, gadolinium, or a combinationthereof.
 12. The endoprosthesis of claim 1, wherein the bioerodiblemagnesium alloy comprises between 3 and 9 weight percent aluminum,between 0.1 and 3.0 weight percent zinc, up to 0.3 weight percentmanganese, and between 0.6 and 1.5 weight percent neodymium, and balancemagnesium.
 13. The endoprosthesis of claim 1, wherein the endoprosthesisis a stent comprising a plurality of struts, wherein the struts have awidth to thickness ratio of less than 1.2.
 14. The endoprosthesis ofclaim 1, wherein the endoprosthesis has a surface finish having an Rasurface roughness of less than 0.2 microns.
 15. The endoprosthesis ofclaim 1, wherein the fully manufactured non-sterile or sterile finishedproduct bare bioerodible magnesium alloy-ceramic composite endoprothesishas a mass loss of less than 10% after 28 days of continuous immersionin non-flowing, agitated Simulated Body Fluid at 37° C., where theSimulated Body Fluid has a volume of at least 10 times an initial volumeof the stent.
 16. A method of processing a bioerodible magnesiumalloy-ceramic nanoparticle composite for a stent comprising: dispersingceramic nanoparticles within a molten magnesium alloy; cooling themolten magnesium alloy and ceramic nanoparticle mixture to form an ingotor billet; and performing at least one high-strain process on the ingotor billet to form a microstructure comprising equiaxed Mg-rich solidsolution-phase grains having an average grain diameter of less than orequal to 5 microns and ceramic nanoparticles in grain boundaries betweenthe equiaxed Mg-rich solid solution-phase grains.
 17. The method ofclaim 16, further comprising holding the ingot or billet at atemperature of between the solvus and liquidus boundaries of the phasediagram for at least 2 hours to homogenize the ingot or billet beforepreforming the at least one high-strain process on the ingot or billet.18. The method of claim 16, wherein the at least one high-strain processis an equal-channel high-strain process preformed at a temperature ofless than 400° C.
 19. The method of claim 18, wherein the ingot orbillet is processed through at least two equal-channel high-strainprocesses at different temperatures, wherein a first equal-channelhigh-strain process occurring at a first time is performed at a highertemperature than a second equal-channel high-strain process occurring ata second time after the first time.
 20. The method of claim 19, whereinthe first equal-channel high-strain process is performed at atemperature of between 250° C. and 400° C. and the second equal-channelhigh-strain process is performed at a temperature of between 150° C. and300° C.